The effects of initiating 28 day periods of treatment with 30 mg/kg (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA) at different times after intravenous inoculation with SIV/DeltaB670 were compared. Twenty-five rhesus monkeys were each inoculated intravenously with 10 100% infectious doses of SIV. Groups of 5 monkeys each received the following subcutaneous treatments, respectively 1) 28 days of physiological saline initiated 24 hr postinoculation (PI); 2) 28 days of PMPA initiated 24 hr PI; 3) 28 days of PMPA initiated 7 days PI; 4) 28 days of PMPA initiated 14 days PI; or 5) PMPA initiated 14 days PI and continued for 4 months. In the saline-treated controls, the onset of serum p27 antigenemia occurred 7-14 days PI and declined to undetectable levels by 21-35 days PI; antigenemia recurrences were detected as early as 70 days PI; proviral DNA became persistently detectable by PCR in PBMC by 7-14 days PI; plasma viral RNA was detected by quantitative competitive PCR of reverse-transcribed DNA (RT-QC-PCR) in 4/5 controls by 7 days PI and in all controls at levels of 105 to 107 copies per ml by 14 days. Initiation of PMPA treatment 24 hr PI had a very potent antiviral effect none of the treated monkeys developed serum antigenemia or detectable proviral DNA in PBMCs during the 28 day treatment period. However, 3/5 treated monkeys became P27 and/or PCR positive on days 42, 84, and 119, respectively; treatment apparently prevented the establishment of infection in 2/5 monkeys in which treatment was initiated 24 hr PI. Initiation of treatment 7 days PI also had a strong antiviral effect antigenemia was decreased and proviral DNA was less consistently detected compared to controls; plasma viral RNA was decreased at least 1-2 logs in all 5 monkeys and to undetectable levels in 2/5 monkeys. Initiation of treatment 14 days PI had less early effect, but continuation of treatment resulted in lower virus burden compared to controls, decreasing plasma viral RNA at least 1-2 logs and falling below detectable limits in 2/5 monkeys. These results demonstrate that PMPA has strong potency against SIV/DeltaB670 in vivo similar to that shown by others for SIVmne and SIVmac251.